The present invention relates to methods of resolving optically active organic compounds, and more particularly to methods of resolving optically active pharmaceutical compounds.
Androgen deprivation is a common treatment for persons with prostate cancer. Various non-steroidal antiandrogens are known for use in the treatment of prostate cancer. For example, bicalutamide, which may be among the most commonly used non-steroidal antiandrogens in the world, is typically used in the treatment of prostate cancer. Bicalutamide is commercially available as Casodex(copyright) (bicalutamide) from Astra Zeneca Pharmaceuticals.
The chemical name of bicalutamide is N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-propanamide,(+xe2x88x92). The structural formula of bicalutamide is: 
The xcex2-carbon atom in the propanamide is a chiral carbon. As a result, bicalutamide is an optically active compound.
Optically active compounds have the ability to rotate the plane of polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (xe2x88x92) are used to denote the optical rotation of the compound (i.e., the direction in which a plane of polarized light is rotated by the optically active compound). The l or (xe2x88x92) prefix indicates that the compound is levorotatory (i.e., rotates the plane of polarized light to the left or counterclockwise) while the d or (+) prefix means that the compound is dextrarotatory (i.e., rotates the plane of polarized light to the right or clockwise). The sign of optical rotation, (xe2x88x92) and (+), is not related to the absolute configuration of the molecule, R and S.
Optically active compounds, such as bicalutamide, exist as a pair of stereoisomers that are identical with the notable exception that they are non-superimposable mirror images of one another. A specific stereoisomer, such as the R isomer, may be referred to as an enantiomer. A mixture of R and S enantiomers may be referred to as a racemic mixture.
Bicalutamide, is presently commercially available as a racemic mixture. The racemic mixture of bicalutamide may be synthesized by various methods including, for example, the methods described in U.S. Pat. No. 4,636,505 to Tucker. Tucker further describes various derivatives and analogs of bicalutamide having antiandrogenic properties. Additionally, Tucker states that this racemic mixture of acylanilide derivatives may be resolved into optically active forms which possess antiandrogenic activity. This method requires complete synthesis of the drug in a racemic mixture followed by esterification, resolution of the diastereomers and hydrolysis to obtain the desired enantiomer. Tucker fails to propose specific methods for achieving this resolution.
U.S. Pat. No. 5,985,868 to Gray proposes synthesizing racemic mixtures of Casodex(copyright) (bicalutamide) using methods as described in U.S. Pat. No. 4,636,505 to Tucker, and obtaining the (R)-(xe2x88x92) enantiomer of Casodex(copyright) (bicalutamide) by resolution of the enantiomers of Casodex(copyright) (bicalutamide) using fractional crystallization or chromatography of diastereomeric esters of chiral acids. Gray notes that other standard methods of resolution such as simple crystallization and chromatographic resolution can also be used. The methods of Gray require complete synthesis of the drug in a racemic mixture. The racemic mixture of the drug is then modified to facilitate resolution, and modified again to yield the active enantiomeric compound. Gray further states that intermediates of Casodex(copyright) (bicalutamide) may be resolved using fractional crystallization or chromatography of diastereomeric esters of chiral acids. However, Gray fails to propose specific intermediates, specific methods, specific esters, and/or specific chiral acids for accomplishing such a resolution. Gray further states that a carboxylic acid precursor, 3-(4-fluorophenyl)-2-hydroxy-2-methylpropanoic acid, which has the following structure: 
may be resolved by fractional crystallization of diastereomeric salts with chiral amines. However, Gray fails to propose specific methods, specific diastereomeric salts, and/or specific chiral amines for accomplishing such a resolution.
In Howard Tucker et al., Resolution of the Nonsteroidal Antiandrogen 4xe2x80x2-Cyano-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl)-propioanilide and the Determination of the Absolute Configuration of the Active Enantiomer, 31 J. Med. Chem. 885-887 (1988), the authors propose preparing chiral bicalutamide by resolution of the thioether: 
Once resolved, the enantiomers of the thioether may be oxidized to the sulfone by known means. The authors also propose resolution of the thioether by reaction of the thioether with (R)-(xe2x88x92)-camphanoyl chloride in pyridine to provide the diastereomeric ester: 
The diastereomeric esters may then be separated by careful flash chromatography on silica gel. The individual pure diasteriomeric isomers may then be hydrolyzed, without racemization, using methanolic sodium hydroxide to yield enantiomeric alcohols: 
wherein E1 is CH3 and E2 is OH for the S configuration, or E1 is OH and E2 is CH3 for the R configuration. These methods require complete synthesis of the drug in a racemic mixture. The racemic mixture of the drug is then modified to facilitate resolution, and modified again to yield the active enantiomeric compound.
Synthesis of the entire drug prior to resolution may result in time and labor costs required for the performance of extra steps, and in the inefficient use of costly starting materials that become components of the less preferred S-enantiomer, which may be disposed of or recycled, resulting in even more expense. Consequently, there is a need in the art for a more streamlined method for preparing substantially enantiomerically pure bicalutamide, which eliminates these additional steps, and which makes efficient use of the starting materials and minimizes waste.
Embodiments of the present invention provide a synthetic method comprising a resolution step which takes place prior to the addition of the most expensive components of the active compound. By resolving an intermediate compound rather than resolving the completely synthesized drug as described above for conventional methods, methods according to the present invention may reduce or eliminate the need for additional post-synthesis procedures and/or reduce or eliminate the need to recycle the less-preferred enantiomer. Additionally, the use of expensive starting materials such as: 
to produce the less-preferred enantiomer may be avoided, which may reduce the costs of producing a substantially pure form of the more-preferred enantiomer.
According to embodiments of the present invention, methods of preparing a substantially pure enantiomer of an acylanilide such as Casodex(copyright) (bicalutamide) and/or its derivatives are provided. The methods include resolving an intermediate compound having the structure of Formula I: 
wherein
R1 is alkyl or haloalkyl having up to 4 carbons;
R2 is alkyl having up to 6 carbon atoms;
R3 is a direct link or alkyl having up to 6 carbon atoms;
R4 is alkyl, alkenyl, hydroxyalkyl or cycloalkyl each of up to 6 carbons; or R4 is phenyl which bears one, two or three substituents independently selected from hydrogen, halogen, nitro, carboxy, carbamoyl and cyano, and alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl, perfluoroalkylsulphonyl, alkoxycarbonyl and N-alkylcarbamoyl each of up to 4 carbon atoms, and phenyl, phenylthio, phenylsulphinyl and phenylsulphonyl; or R4 is naphthyl; or R4 is a 5- or 6-membered saturated or unsaturated heterocyclic which contains one, two or three heteroatoms selected from oxygen, nitrogen and sulfur, which heterocyclic may be a single ring or may be fused to a benzo-ring, and which heterocyclic is unsubstituted or bears one or two halogen, cyano or amino, or alkyl, alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl each of up to 4 carbon atoms, or oxy or hydroxy substituents, or which if sufficiently saturated may bear one or two oxo substituents; and
X1 is oxygen, sulfur, sulphinyl (xe2x80x94SOxe2x80x94), sulphonyl (xe2x80x94SO2xe2x80x94), imino (xe2x80x94NHxe2x80x94) or alkylimino (xe2x80x94NR5xe2x80x94) where R5 is alkyl having up to 6 carbon atoms.
The resolved intermediate compound of Formula I is then treated under conditions sufficient to provide a substantially pure enantiomer of the acylanilide.
In some embodiments of the present invention, the step of resolving an intermediate compound of Formula I includes crystallizationally resolving the intermediate compound of Formula I. The crystallizationally resolving step includes contacting the intermediate compound of Formula I with a chiral base to provide a diastereomeric mixture of a chiral salt, crystallizationally resolving the diastereomeric mixture of the chiral salt to provide a substantially pure enantiomer of the chiral salt, and recovering a substantially pure enantiomer of the intermediate compound of Formula I. The contacting step preferably includes contacting the intermediate compound of Formula I with (xe2x88x92)-cinchonidine to provide a diastereomeric mixture of the chiral salt. The step of crystallizationally resolving the diastereomeric mixture of the chiral salt preferably includes contacting the diastereomeric mixture of the chiral salt with a solvent system comprising, for example, methylene chloride and diethyl ether. In other embodiments, the step of resolving an intermediate compound of Formula I may include high performance liquid chromatographically resolving the intermediate compound of Formula I.
The resolved intermediate is preferably contacted with an aniline compound having the structure of Formula II: 
wherein
R6 is cyano, carbamoyl, nitro, fluoro, chloro, bromo, iodo, or hydrogen, or alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl or perfluoroalkylsulphonyl each having up to 4 carbon atoms, or phenylthio, phenylsulphinyl or phenylsulphonyl;
R7 is cyano, carbamoyl, nitro, fluoro, chloro, bromo or iodo, or alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl or perfluoroalkylsulphonyl each of having up to 4 carbon atoms; or phenylthio, phenylsulphinyl or phenylsulphonyl; and
R8 is hydrogen or halogen;
under conditions sufficient to provide a substantially pure enantiomer of an acylanilide. The substantially pure enantiomer of the acylanilide is preferably the (R)-enantiomer of Casodex(copyright) (bicalutamide).
By resolving intermediates rather than resolving completely synthesized drugs, methods according to the present invention may provide more cost effective ways of synthesizing substantially pure enantiomers of acylanilides such as Casodex(copyright) (bicalutamide) and derivatives thereof than are provided by conventional resolution techniques. For example, methods according to the present invention may be more cost effective because they resolve the intermediates prior to reacting them with the expensive aniline component, avoiding unwanted costs associated with the expensive aniline component, which is typically wasted in the production of the less-preferred enantiomer.